Temozolomide (CAS: 85622-93-1)

Temozolomide is an oral chemotherapy drug. It is an alkylating agent used for the

treatment of Grade IV astrocytoma — an aggressive brain tumor, also known as

glioblastoma multiforme — as well as for treating melanoma, a form of skin cancer.

Temozolomide is also indicated for relapsed Grade III anaplastic astrocytoma and not

indicated for, but as of 2011 used to treat oligodendroglioma brain tumors in some

countries, replacing the older (and less well tolerated) PCV (Procarbazine-

Lomustine-Vincristine) regimen.

The agent was developed by Malcolm Stevens and his team at Aston University in

Birmingham, Temozolomide is a prodrug and an imidazotetrazinederivative of the

alkylating agent dacarbazine. It has been available in theUSsince August 1999, and

in other countries since the early 2000s.

The therapeutic benefit of temozolomide depends on its ability to alkylate/methylate

DNA, which most often occurs at the N-7 or O-6 positions of guanineresidues. This

methylation damages the DNA and triggers the death of tumor cells. However, some

tumor cells are able to repair this type of DNA damage, and therefore diminish the

therapeutic efficacy of temozolomide, by expressing a protein O6-alkylguanine DNA

alkyltransferase (AGT) encoded in humans by the O-6-methylguanine-DNA

methyltransferase (MGMT) gene. In some tumors, epigenetic silencing of the MGMT

gene prevents the synthesis of this enzyme, and as a consequence such tumors are more

sensitive to killing by temozolomide. Conversely, the presence of AGT protein in brain

tumors predicts poor response to temozolomide and these patients receive little benefit

from chemotherapy with temozolomide.

Structure and mechanism

Temozolomide (sometimes referred to as TMZ) is an imidazotetrazine derivative of the

alkylating agent dacarbazine. It undergoes rapid chemical conversion in the systemic

circulation at physiological pH to the active compound, 3-methyl-(triazen-1-yl)imidazole

-4-carboxamide (MTIC). Temozolomide exhibits schedule-dependent antineoplastic activity

by interfering with DNA replication. Temozolomide has demonstrated activity against

recurrentglioma. In a recent randomized trial, concomitant and adjuvant temozolomide

chemotherapy with radiation significantly improves, from 12.1 months to 14.6 months,

progression free survival and overall survival in glioblastoma multiforme patients.